U.S. patent number 11,377,420 [Application Number 16/910,582] was granted by the patent office on 2022-07-05 for compositions and methods for making donor-acceptor azetines.
This patent grant is currently assigned to Board of Regents, The University of Texas System. The grantee listed for this patent is Board of Regents, The University of Texas System. Invention is credited to Michael Patrick Doyle, Kostiantyn Oleksandrovich Marichev.
United States Patent |
11,377,420 |
Doyle , et al. |
July 5, 2022 |
Compositions and methods for making donor-acceptor azetines
Abstract
A highly effective synthetic route to produce donor-acceptor
azetines through the highly enantioselective [3+1]-cycloaddition of
silyl-protected enoldiazoacetates with aza-ylides using chiral
copper(I) catalysis is provided. In one embodiment, the 2-azetidine
cycloaddition products undergo generation of 3-azetidinones by
reactions with nucleophiles that produce a broad spectrum of
peptide products by the retro-Claisen reaction provided by facile
strain with high efficacy and complete retention of enantiopurity.
This ring opening reaction uncovers a new methodology for the
attachment of chiral peptide units to a variety of amines and
alcohols, and tolerates a broad scope of nucleophiles including
naturally occurring amines, alcohols, amino acids, and other
nitrogen based nucleophiles.
Inventors: |
Doyle; Michael Patrick (San
Antonio, TX), Marichev; Kostiantyn Oleksandrovich (San
Antonio, TX) |
Applicant: |
Name |
City |
State |
Country |
Type |
Board of Regents, The University of Texas System |
Austin |
TX |
US |
|
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Assignee: |
Board of Regents, The University of
Texas System (Austin, TX)
|
Family
ID: |
1000006411349 |
Appl.
No.: |
16/910,582 |
Filed: |
June 24, 2020 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20200399214 A1 |
Dec 24, 2020 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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62865525 |
Jun 24, 2019 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07C
229/46 (20130101); C07D 205/06 (20130101); C07J
41/0055 (20130101); C07D 219/12 (20130101); B01J
31/22 (20130101); B01J 2531/16 (20130101) |
Current International
Class: |
C07D
205/06 (20060101); B01J 31/22 (20060101); C07J
41/00 (20060101); C07C 229/46 (20060101); C07D
219/12 (20060101) |
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|
Primary Examiner: Chen; Po-Chih
Attorney, Agent or Firm: Smith Gambrell Russell LLP
Jarecki-Black; Judy Sabnis; Ram W.
Government Interests
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH
This invention was made with government support under CHE-1559715
awarded by the National Science Foundation. The government has
certain rights in the invention.
Parent Case Text
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims benefit of and priority to U.S. Provisional
Application No. 62/865,525 filed on Jun. 24, 2019, which is
incorporated by reference in its entirety.
Claims
We claim:
1. A method for synthesizing donor-acceptor azetines, comprising:
reacting an enoldiazoacetate with an aza-ylide in the presence of a
copper catalyast to produce a donor-acceptor azetine.
2. The method of claim 1, wherein the enoldiazoacetate is
##STR00018##
3. The method of claim 1, wherein the aza-ylide is
N-arylsulfilimine.
4. The method of claim 1, wherein the copper catalyst comprises
Cu(MeCN).sub.4PF.sub.6.
5. The method of claim 1, wherein the donor acceptor azetine is
methyl
1-(4-chlorophenyl)-3-[(triisopropylsilyl)oxy]-1,4-dihydroazetine-2-carbox-
ylate.
6. The method of claim 1, wherein the reaction further comprises
sabox ligand, ##STR00019##
7. A method for producing amino acid derivatives comprising:
synthesizing donor-acceptor azetines according to the method of
claim 1; and selectively coupling the donor-acceptor azetine with
nitrogen or oxygen nucleophile via 3-azetidinones to form amino
acid derivatives.
8. The method of claim 7, wherein the enoldiazoacetate is
##STR00020##
9. The method of claim 7, wherein the aza-ylide is
N-arylsulfilimine.
10. The method of claim 7, wherein the copper catalyst comprises
Cu(MeCN).sub.4PF.sub.6.
11. The method of claim 7, wherein the donor acceptor azetine is
methyl
1-(4-chlorophenyl)-3-[(triisopropylsilyl)oxy]-1,4-dihydroazetine-2-carbox-
ylate.
12. The method of claim 7, wherein the reaction further comprises
sabox ligand, ##STR00021##
Description
TECHNICAL FIELD OF THE INVENTION
Aspects of the invention are generally directed to the field of
chemistry, in particular the synthesis of novel chiral
donor--acceptor azetines.
BACKGROUND OF THE INVENTION
Coupling reactions of amines and alcohols are of central importance
for applications in chemistry and biology. These transformations
typically involve the use of a reagent, activated as an
electrophile, onto which nucleophile coupling results in the
formation of a carbon-nitrogen or a carbon-oxygen bond. Several
promising reagents and procedures have been developed to achieve
these bond forming processes in high yields with excellent
stereocontrol, but few offer direct coupling without the
intervention of a catalyst.
Irreversible ring opening of the strained 2-azetidinone
four-membered ring, which is one of the key biomolecular events
during both the antibiotic action of .beta.-lactams and their
inhibition by .beta.-lactamases (Fisher, J. F. et al., Chem. Rev.
105, 395-424 (2005)), is a model for nucleophile coupling. The
chemically controlled ring opening of 2-azetidinones with cleavage
of the carbonyl-nitrogen bond is a powerful tool for the synthesis
of heterocycles, 3-amino acids, and their derivatives (Palomo C.
& Oiarbide M. (2010) In: Banik B. (eds) Heterocyclic Scaffolds
I. Topics in Heterocyclic Chemistry, vol 22. Springer, Berlin,
Heidelberg Page MI The chemistry of .beta.-lactams. Chapman and
Hall, London); Crowder, M. W. et al., Acc. Chem. Res., 39, 721-728
(2006); Kamath, A. & Ojima, I., Tetrahedron, 68, 10640-10664
(2012)). Their versatility in chemistry and biology has propelled
them to high levels of scientific and pharmacological importance.
3-Azetidinones, by contrast, are less well established (Dejaegher,
Y., et al., Chem. Rev, 102, 29-60 (2002)) even though they have the
potential for nucleophilic carbonyl-carbon cleavage to form amine
derivatives (Eq. 1) if an activating electron-withdrawing group
(EWG) is located at the 2-position; but the key to realizing this
potential lies in the design of a 3-azetidinone capable of
nucleophile coupling.
##STR00001## A classic approach to nucleophile coupling is the
retro-Claisen reaction of .beta.-ketoesters (Jukic, M., et al.
Curr. Org. Synth. 9, 488-512 (2012)) that would require the
construction of previously unreported 2-carboxylate substituted
3-azetidinones, but the basic methods available for their formation
are the same as those desired for their ring-opening coupling which
is favoured by ring strain (Gianatassio, R. et al. Science, 351,
241-246 (2016); Lopchuk, J. M. et al. J. Am. Chem. Soc., 139,
3209-3226 (2017); Fawcett, A., et al., Nat. Chem., 11, 117-122
(2019); Fawcett, A., et al., J. Am. Chem. Soc., 141, 4573-4578
(2019)). Alternative methodologies proceeding to
2-azetine-2-carboxylate structures were applied to the formation of
the 3-azedidinone analogues, either through [2+2]-cycloaddition
(Pang, S. et al., ACS Catal. 8, 5193-5199 (2018)), from
3-substituted 2-azetines (lithiation) (Hodgson, D. M. &
Kloesges, J. Angew. Chem. Int. Ed. 49, 2900-2903 (2010); Hodgson,
D. M. et al., Org. Lett. 16, 856-859 (2014); Burkhard, J. A. &
Carreira, E. M. Org. Lett. 10, 3525-3526 (2008); Burkhard, J. A. et
al. Angew. Chem. Int. Ed. 49, 3524-3527 (2010); Burkhard, J. A. et
al. Org. Lett. 12, 1944-1947 (2010)), or with N-Boc-3-azetidinone
(coupling reactions) (Baumann, A. N. et al. Org. Lett. 19,
5681-5684 (2017)), but these methods were not suitable for
2-carboxylate derivatives. In addition, attempted
copper(I)-catalyzed [3+1] cycloaddition of alkenyldiazoacetates and
iminoiodinanes to form the requisite 3-azetidinone was also
unsuccessful (Barluenga, J. et al. Chem.--Eur. J. 18, 9221-9224
(2012)).
Therefore, it is an object of the invention to provide new methods
and reagents for producing donor-acceptor azetines.
SUMMARY OF THE INVENTION
A highly effective synthetic route to produce donor-acceptor
azetines through the highly enantioselective [3+1]-cycloaddition of
silyl-protected enoldiazoacetates with aza-ylides using chiral
copper(I) catalysis is provided. In one embodiment, the 2-azetidine
cycloaddition products undergo generation of 3-azetidinones by
reactions with nucleophiles that produce a broad spectrum of
peptide products by the retro-Claisen reaction provided by facile
strain with high efficacy and complete retention of enantiopurity.
This ring opening reaction uncovers a new methodology for the
attachment of chiral peptide units to a variety of amines and
alcohols, and tolerates a broad scope of nucleophiles including
naturally occurring amines, alcohols, amino acids, and other
nitrogen-based nucleophiles.
One embodiment provides a method for producing amino acid
derivatives from donor-acceptor azetines by their selective
coupling with nitrogen and oxygen nucleophiles via 3-azetidinones
to form amino acid derivatives.
Another embodiment provides a method for synthesizing
donor-acceptor azetines, by reacting an enoldiazoacetate with an
aza-ylide in the presence of a copper catalyst to produce a
donor-acceptor azetine. In another embodiment the aza-ylide
includes, but is not limited to N-arylsulfilimine. In still another
embodiment, the copper catalyst includes, but is not limited to
Cu(MeCN).sub.4PF.sub.6.
In some embodiments, the method includes a modified sidearm
bisoxazoline (sabox) ligand.
Another embodiment provides a compound according to the following
formula:
##STR00002##
Another embodiment provides a compound according to the following
formula:
##STR00003##
Another embodiment provides a compound according to the following
formula:
##STR00004##
Still another embodiment provides a compound according to the
following formula:
##STR00005##
BRIEF DESCRIPTION OF THE DRAWINGS
FIGS. 1A-1Q shows a panel of chiral peptides using ring opening
reactions of 2-azetine-2-carboxylates 3 with amines. Reaction
conditions: .sup.a0.2 mmol of 3, 0.5 mmol of amine, 4.0 mL of DCM,
r.t., 48 h; .sup.b0.2 mmol of 3, 0.8 mmol of amine, 4.0 mL of
THF/water 1:1 (v/v), r.t., 12 h; .sup.c0.2 mmol of 3, 0.5 mmol of
amine, 4.0 mL of DCM, r.t., 4 days; .sup.d0.2 mmol of 3, 0.6 mmol
of amine, 4.0 mL of DCE, 65.degree. C., 24 h; .sup.e0.2 mmol of 3,
0.6 mmol of amine, 3.0 mL of MeNO2, r.t., 12 h.
FIGS. 2A-2G shows a panel of chiral diesters synthesized using ring
opening reactions of 2-azetine-2-carboxylates 3 with alcohols.
Reaction conditions: .sup.a0.2 mmol of 3, 5.0 mL of MeOH,
65.degree. C., 2 h; .sup.b0.2 mmol of 3, 5.0 mL of EtOH, 65.degree.
C., 24 h; .sup.c0.2 mmol of 3, 0.8 mmol of alcohol, 3.0 mL of THF,
65.degree. C., 24 h; .sup.d0.2 mmol of 3, 0.8 mmol of alcohol, 3.0
mL of 1,4-dioxane/water 2:1 (v/v), 65.degree. C., 24 h.
FIGS. 3A-3G shows a panel of compounds synthesized using ring
opening reactions of 2-azetine-2-carboxylate 3c with other
nucleophiles. Reaction conditions: .sup.a0.2 mmol of 3, 0.3 mmol of
TBAF, 4.0 mL of DCM, r.t., 2 h; .sup.b0.2 mmol of 3, 0.6 mmol of
phenylhydrazine, 4.0 mL of DCE, 50.degree. C., 12 h; .sup.c0.2 mmol
of 3, 1.0 mmol of the nucleophile, 4.0 mL of THF, r.t., 12 h;
.sup.d0.2 mmol of 3, 0.8 mmol of guanidine, 4.0 mL of THF/water 1:1
(v/v), r.t., 12 h; .sup.e0.2 mmol of 3, 0.6 mmol of
4-nitrophenylhydrazine, 3.0 mL of MeNO.sub.2, r.t., 24 h.
FIG. 4A shows a proposed reaction mechanism for nucleophilic ring
opening of 2-azetine-2-carboxylates 3. FIG. 4B shows a deuterium
incorporation experimental scheme. FIG. 4C shows a proton-deuterium
exchange with MeOD scheme.
FIG. 5A-5B shows a representative example of Suzuki-Miyaura
cross-coupling of a ring opened product. FIG. 5C shows the
attachment of fluorescent units to chiral peptides made from
functionalization of ring opened products. FIGS. 5D-5F shows the
functionalization of cholesterol and ergocalciferol (vitamin
D.sub.2) using chiral peptide attachment. .sup.aObtained from 26
(0.2 mmol) and a natural product (0.22 mmol) using
N,N'-dicyclohexylcarbodiimide (DCC, 0.24 mmol) and
4-dimethylaminopyridine (DMAP, 0.03 mmol) at room temperature.
DETAILED DESCRIPTION OF THE INVENTION
I. Definitions
As used herein, the singular forms "a," "an," and "the" include
plural referents unless the context clearly dictates otherwise. For
example, reference to "the method of treatment" includes reference
to equivalent steps and methods known to those skilled in the art,
and so forth.
Recitation of ranges of values herein are merely intended to serve
as a shorthand method of referring individually to each separate
value falling within the range, unless otherwise indicated herein,
and each separate value is incorporated into the specification as
if it were individually recited herein.
The term "carrier" refers to an organic or inorganic ingredient,
natural or synthetic, with which the active ingredient is combined
to facilitate the application.
The term "pharmaceutically acceptable" means a non-toxic material
that does not interfere with the effectiveness of the biological
activity of the active ingredients.
The term "pharmaceutically-acceptable carrier" means one or more
compatible solid or liquid fillers, dilutants or encapsulating
substances which are suitable for administration to a human or
other vertebrate animal.
The term "effective amount" or "therapeutically effective amount"
means a dosage sufficient to provide treatment a disorder, disease,
or condition being treated, or to otherwise provide a desired
pharmacologic and/or physiologic effect. The precise dosage will
vary according to a variety of factors such as subject-dependent
variables (e.g., age, immune system health, etc.), the disease, and
the treatment being effected.
The terms "individual," "subject," and "patient" are used
interchangeably herein, and refer to a mammal, including, but not
limited to, humans, rodents, such as mice and rats, and other
laboratory animals.
II. Ring-Opened Products from Donor-Acceptor Azetine Compounds
Ring-opened products from donor-acceptor azetine compounds and
methods of making the same are provided herein. Exemplary compounds
are disclosed below.
A. Compounds
In one embodiment, ring-opened products from donor-acceptor azetine
compounds are synthesized by ring opening reactions of
2-azetine-2-carboxylates 3 with amines. In one embodiment such
compounds are selected from the group consisting of:
##STR00006## ##STR00007##
In another embodiment, ring-opened products from donor-acceptor
azetine compounds are synthesized by ring opening reactions of
2-azetine-2-carboxylates 3 with alcohols. In one embodiment such
compounds are selected from the group consisting of:
##STR00008##
Another embodiment provides ring-opened products from
donor-acceptor azetine compounds that are synthesized by ring
opening reactions of 2-azetine-2-carboxylates 3c with other
nucleophiles. In one embodiment such compounds are selected from
the group consisting of:
##STR00009##
1. Conjugates
Some embodiments provide conjugates of the disclosed ring-opened
products from donor-acceptor azetine compounds wherein the
ring-opened products from donor-acceptor azetine compounds is
conjugated to a second compound including but not limited to
targeting moieties, proteins, peptides, antibodies, probes,
markers, or labels. The moieties can be conjugated to the compounds
to serve as detection agents, to deliver the compounds to specific
cells or tissues, to deliver the compounds to specific subcellular
locations, or a combination thereof.
In one embodiment, the disclosed ring-opened products from
donor-acceptor azetine compounds are conjugated to one or more
detection agents. Exemplary detection agents include but are not
limited to fluorophores, isotope markers, colorimetric labels,
biotin/avidin, fluorogens, or mass tags.
One embodiment provides ring-opened products from donor-acceptor
azetine compounds containing fluorine atoms that are synthesized
through Suzuki-Miyaura sp.sup.2-sp.sup.2 cross-coupling with
diamide. The compounds are as follows:
##STR00010##
One embodiment provides ring-opened products from donor-acceptor
azetine compounds conjugated to a fluorescent unit using the ring
opening reaction of azetine 3c with 4-aminoacridine as a
fluorophore-carrying nucleophile. The compounds are as follows:
##STR00011##
In one embodiment, the disclosed compounds are conjugated with a
moiety that delivers the compounds to specific cells or tissues, or
to specific subcellular locations. In such an embodiment, the
compound is conjugated with a moiety that targets a protein or
receptor that is present on the desired tissue, cell type, or
subcellular location. In one embodiment, the moiety is an antibody
that binds to a receptor on the target cell. In another embodiment,
the moiety is a small molecule that binds to a receptor on the
target cell. In yet another embodiment, the moiety a sugar
molecule, a glycolytic enzyme, or folate. Exemplary compounds are
as follows:
##STR00012##
In one embodiment, the disclosed ring-opened products from
donor-acceptor azetine compounds are conjugated to a biomolecule.
In certain embodiments, the biomolecule includes but is not limited
to a protein, antibody, small biomolecule, biotin, or biological
ligands. The term "biological ligands" refers to protein receptors,
lipid receptors, polysaccharide receptors, lipopolysaccharide
receptors, glycolipids, and their biological ligands. The protein
receptor can be intracellular or express on the cell surface.
III. Production of Ring-Opened Products From Donor-Acceptor
Azetines
A. [3+1]-Cycloaddition: Reaction Development.
Application of N-acylimido sulfur ylides (Yoshimura, T. &
Omata, T. J. Org. Chem. 41, 1728-1733 (1976); Bizet, V., et al.
Angew. Chem. Int. Ed. 53, 5639-5642 (2014); Hayashi, R. et al.
Chem.--Eur. J. 23, 61-64 (2017)) and enoldiazoacetates to the same
catalysts and conditions that were successful with their carbon
analogues was unsuccessful even at elevated temperatures due to a
lack of reactivity of the imido ylide. Use of N-arylimido sulfur
ylides (S,S-disubstituted N-arylsulfilimines) (Gilchrist, T. L.
& Moody, C. J. Chem. Rev. 77, 409-435 (1977); Garcia Ruano, J.
L. et al. Science of Synthesis, 39, 245-390 (2007); Tian, X. et al.
Angew. Chem. Int. Ed., 58, 3589-3593 (2019)), however, allowed
cycloaddition to proceed smoothly at room temperature. As
previously described for the corresponding [3+1]-cycloaddition that
formed donor-acceptor cyclobutene derivatives (Deng, Y., et al.,
Angew. Chem. Int. Ed. 56, 7479-7483 (2017)), only copper(I)
catalysis was effective for this transformation; and
Cu(MeCN).sub.4PF.sub.6 was the catalyst of choice in the formation
of 2-azetines. Product yields were the highest in dichloromethane,
and diphenylsulfur ylides gave higher product yields than their
dimethyl or methylphenyl analogues. Reactions were performed at
room temperature to avoid electroreversion of the azetine (Lopez,
S. A. & Houk, K. N. J. Org. Chem. 79, 6189-6195 (2014);
Shindoh, N., et al., J. Am. Chem. Soc. 133, 8470-8473 (2011);
Mangelinckx, S. et al. J. Org. Chem. 73, 5481-5488 (2008)).
[3+1]-Cycloaddition occurred with the
triisopropylsilyl(TIPS)-protected enoldiazoacetate but not with the
tert-butyldimethylsilyl(TBS)-protected enoldiazoacetate. With these
optimizations methyl
N-(p-chlorophenyl)-3-OTIPS-2-azetine-2-carboxylate 3 was formed in
80% isolated yield (Eq. 2).
##STR00013##
While in the foregoing specification this invention has been
described in relation to certain embodiments thereof, and many
details have been put forth for the purpose of illustration, it
will be apparent to those skilled in the art that the invention is
susceptible to additional embodiments and that certain of the
details described herein can be varied considerably without
departing from the basic principles of the invention.
To introduce chirality into the 2-azetine-2-carboxylate a
substituent at the terminal vinyl position of enoldiazoacetate 1 is
required. Previous reports on enoldiazoacetates described the
synthesis and uses of only two TBS- and TIPS-protected
enoldiazoacetates having terminal vinyl substituents (4-Me and
4-Ar) (Deng, Y., et al., Angew. Chem. Int. Ed. 56, 7479-7483
(2017); Wang, X. et al. Adv. Synth. & Catal. 358, 1571-1576
(2016); Deng, Y., et al., Chem. Commun., 51, 12924-12927 (2015);
Xu, X., et al., Org. Lett., 17, 790-793 (2015); Xu, X., et al.,
Chem. Commun., 49, 10287-10289 (2013); Qian, Y. et al., Angew.
Chem. Int. Ed., 51, 5900-5903 (2012); Zhu, C., et al., Angew. Chem.
Int. Ed., 55, 11867-11871 (2016); Lian, Y., et al., Angew. Chem.
Int. Ed., 50, 9370-9373 (2011)), and both of their geometrical
isomers were formed in the case of TIPS-derivatives. Provided
herein is a synthetic solution to this challenge that allows
dominant formation of the Z-isomer (Z:E=>20:1) for these
substituted enoldiazoacetates (Dong, K., et al., Synlett, 30
(2019)) and, only the Z-isomer undergoes [3+1]-cycloaddition.
To effect asymmetric induction for 2-azetine ring formation, methyl
(Z)-3-OTIPS-2-diazo-3-pentenoate 1b with N-(p-chlorophenyl)imido
diphenylsulfur ylide 2a were initially selected and the
cycloaddition reaction was performed under the optimized conditions
with catalysis by Cu(MeCN).sub.4PF.sub.6 coordinated to chiral
sabox ligand L1 (Eq. 3).
##STR00014##
The use of ligand L1 resulted in the highest yield and
enantioselectivity (71% yield, 75% ee). Although the yield and
enantioselectivity for 3b obtained with L1 were only moderate,
substituents were varied at the 4-position of enoldiazoacetate 1 in
order to determine if these substituents influence product
formation and selectivity. A general procedure was established for
the introduction of substituents to the 4-position of
enoldiazoacetate 1 (Dong, K., et al., Synlett, 30 (2019)); and,
using 2a as the optimum sulfilimine, [3+1]-cycloaddition was
performed under optimum conditions. The initial reaction of 1b
(Z:E=3:1) with a 50% molar excess of 2a showed complete loss of
Z-1b but retention of E-1b and a 75% ee for 3b (Eq. 3). This
observation prompted the use of an excess of the 4-substituted
enoldiazoacetate over sulfilimine 2a to reflect the actual
stoichiometric amount of the Z-isomer in the Z-1/E-1 mixture. When
the reaction of 1b (Z:E=>20:1) with 2a was repeated using a
(1.2):1 ratio 1b/2a [vs. 1: (1.5) reported in Eq. 3], this
modification resulted in an increased yield of 3b to 82% (entry 1,
Table 1) with the same ee value of 75%. Changing the methyl
substituent at the 4-position of 1 to ethyl not only improved the
enantioselectivity for the [3+1]-cycloaddition to 90% ee but also
resulted in an increase of the isolated yield (92%) of 3c (entry 2,
Table 1). Further elaboration of the substituent at the 4-position
with benzyl (3d), isopropyl (3e), and n-octyl (3f) under the same
conditions led to a modest decrease in reactivity, apparently due
to steric effects, and lowered product yields, but % ee values were
comparable to or higher than that of 3c (90-97% ee).
##STR00015##
TABLE-US-00001 TABLE 1 Scope of enoldiazoacetates: effect of the
aliphatic chain at the 4-position of enoldiazoacetate 1 entry.sup.a
R yield 3 (%).sup.b ee (%).sup.c 1 Me 3b 82 75 2 Et 3c 92 90
3.sup.d Bn 3d 73 90 4.sup.d iPr 3e 70 92 5.sup.d n-C.sub.8H.sub.17
3f 63 97 .sup.aAll reactions were carried out on a 0.20 mmol scale
in 4.0 mL DCM: 2a (0.20 mmol), 1a (0.24 mmol). .sup.bIsolated yield
after flash-chromatography. .sup.cDetermined by chiral HPLC
analysis. .sup.dReaction time was 72 h.
To identify a possible further improvement in enantiocontrol the
influence of the carboxylate ether group (size and electronic
effects) of enoldiazoacetates 1 was investigated. With an Et
(R.sup.1) substituent at the 4-position (Table 2) introduction of
an isopropyl group as R.sup.2 (1g) resulted in a decrease of
azetine yield without a change in enantioselectivity (entry 1;
Table 2). Notably, the corresponding tert-butyl enoldiazoacetate
(R.sup.2=tBu) resulted in only trace amounts of the
[3+1]-cycloaddition product. Neither benzyl (1h) nor 4-bromobenzyl
(1i) substituted enoldiazoacetates provided any noticeable
improvement in enantiocontrol (90-92% ee) and yields (87-90%)
(entries 2,3; Table 2). Surprisingly, the p-methoxybenzyl (PMB)
ester provided a remarkable level of enantiocontrol (99% ee) and
also produced 3j in 95% yield (entry 4; Table 2). A very similar ee
value (98% ee) was obtained for the 3,4,5-trimethoxybenzyl
derivative 3k, however the reaction time for this reaction was
extended to 48 h in order to achieve full conversion (entry 5;
Table 2). As expected, the presence of the electron withdrawing
CF.sub.3 group at the 4-position of phenyl ring (1l) resulted in
decrease of both the yield (73%) and enantioselectivity (87% ee) of
azetine 3l. To determine that the effect of the PMB group as
R.sup.2 might be general p-methoxybenzyl
3-OTIPS-2-diazo-3-pentenoate 1m was prepared and the
[3+1]-cycloaddition reaction was performed (entry 7; Table 2):
enantioselectivity was improved from 75% (3b, R.sup.2=Me) to 88% ee
(3m, R.sup.2=PMB).
##STR00016##
TABLE-US-00002 TABLE 2 Scope of enoldiazoacetates: effect of the
carboxylate group entry.sup.a R.sup.1 R.sup.2 yield 3 (%).sup.b ee
(%).sup.c 1 Et iPr 3g 82 89 2 Et Bn 3h 87 92 3 Et 4-BrBn 3i 90 90 4
Et 4-OMeBn 3j 95 99 5.sup.d Et 3,4,5-triOMeBn 3k 70 98 6 Et
4-CF.sub.3Bn 3l 73 87 7 Me 4-OMeBn 3m 77 88 .sup.aAll reactions
were carried out on a 0.20 mmol scale in 4.0 mL DCM: 2a (0.20
mmol), 1a (0.24 mmol). .sup.bIsolated yield after
flash-chromatography. .sup.cDetermined by chiral HPLC analysis.
.sup.dReaction time was 48 h.
B. Nucleophilic Ring Opening Reactions of Donor-Acceptor
Azetines.
That ring opening would be a facile process of these donor-acceptor
azetines was not initially obvious. Five- and six-membered ring
silyl-protected .beta.-enolcarboxylates are well known to form
0-ketoesters after desilylation (Smith, A. G. & Davies, H. M.
L., J. Am. Chem. Soc., 134, 18241-18244 (2012); Deng, Y., et al.,
Angew. Chem. Int. Ed., 55, 10108-10112 (2016); Xu, X., et al.,
Chem. Commun. 49, 10287-10289 (2013); Xu, X., et al., Angew. Chem.
Int. Ed. 51, 9829-9833 (2012)). However, when azetine 3b was
treated with the classic TBAF to effect desilylation, a mixture of
ring opened products was obtained under typically mild conditions.
This observation suggested that initial enolate formation had
occurred and that subsequent nucleophilic reaction on the
.beta.-keto ester or its equivalent effected strain-induced ring
opening. To determine the extent of nucleophilic ring opening with
strain release of donor-acceptor azetines were treated with a
variety of nitrogen and oxygen nucleophiles. It was assumed that
TIPS group removal from 2-azetine-2-carboxylates 3 occurs under
mild conditions to generate the 3-azetidinone carboxylate
structure, which then undergoes ring opening with the excess of a
nucleophile (Eq. 6). This concept of strain release through
carbon-carbon .sigma.-bond cleavage from 3-azetidinone carboxylates
bond is uncovered in this work for the first time, and this
nucleophile coupling opens doors to enormous opportunities in the
synthesis of new chiral peptides and relevant substances of
biological interest with high optical purity.
##STR00017## 2-Azetine-2-carboxylates 3c and 3j were the substrates
of choice in most cases because of their availability.sup.26 and
optical purity (90% and 99% ee, respectively). Initial assessment
of reactivity was carried out by reactions with 2.5 equiv. of
benzylamine in DCM at room temperature (FIGS. 1A-1P). Ring opened
products that contain one peptide bond were formed within 48 h in
near quantitative isolated yields (4, 95% and 5, 96%). Moreover,
the complete retention of optical purity in the products of the
nucleophile coupling reactions were observed. The ester
functionality remained intact under these reaction conditions even
when 4 equiv. of benzylamine was used. However, consistent with
nucleophilic reactions that form ionic intermediates (Shawali, A.
S. A. S. & Biechler, S. S., J. Am. Chem. Soc. 89, 3020-3026
(1967); Adalsteinsson, H. & Bruice, T. C., J. Am. Chem. Soc.,
120, 3440-3447 (1998)), changing the polarity of the solvent played
a significant role in increasing the reactivity of 3c towards
benzylamine, so that with 4 equiv. of benzylamine or
4-bromobenzylamine in THF/water 1:1 (v/v) chiral diamide
derivatives 6a,b were formed in high yields (93% and 85%,
respectively) within 12 h. This was an unexpected observation
because the classic reaction of an ester with amines is very
sluggish at room temperature. A control reaction of monoamide 4
with an excess of benzylamine (2 equiv.) resulted in a quantitative
yield of diamide 6 in 12 h. Apparently, formation of the first
amide unit activates the carbonyl group of the ester via
intramolecular hydrogen bonding in water (polar protic solvent),
and therefore favors the nucleophilic substitution by benzylamine
on the ester group. The regioselectivity of the ring opening
reaction of 3c with N-cyclohexyl-1,3-propanediamine
(primary-secondary diamine) was investigated. Formation of the
amide bond occurred exclusively at the primary amine position of
the diamine, and the monoamination product 7 was isolated in 92%
yield. Inspired by the results with benzylamine, the remarkable
levels of regioselectivity with N-cyclohexyl-1,3-propanediamine,
and the solvent effect on product formation, reactions of
2-azetines 3c and 3f with biologically relevant amines and natural
amino acids were examined. Monoamide derivatives of tryptamine (8
and 9), benzyl-protected L-proline (10), and glutamic acid diethyl
ester (14), for example, were obtained in 84-88% isolated yields in
reactions carried out in dichloromethane. Ring opening of 3c with a
natural polyamine, spermine, in DCM occurred selectively at the
terminal primary amine position of spermine but, unlike with other
amines, formed chiral diamide 15 as the major product (63% yield).
The reaction of 3c with tert-butylamine, a sterically hindered
primary amine, occurred with similar efficacy as that with
benzylamine (92% yield). Treatment of azetine 3c with aromatic
amines, which are weaker nucleophiles, showed negligible conversion
in DCM at room temperature, but heating 3c with aniline (3 equiv.)
at 65.degree. C. in 1,2-dichloroethane (DCE) for 24 h resulted in
ring opening nucleophilic coupling; however, 13a was formed in only
65% yield together with the product from the known thermal
electrocyclic ring opening of 3c (Lopez, S. A. & Houk, K. N.,
J. Org. Chem. 79, 6189-6195 (2014); Shindoh, N., et al., J. Am.
Chem. Soc. 133, 8470-8473 (2011); Mangelinckx, S. et al. J. Org.
Chem. 73, 5481-5488 (2008)). Use of electron-rich
4-(dimethylamino)aniline with 3c in nitromethane at room
temperature increased the yield of the ring opened product to 93%
(13b). The reaction of 3c with (R)-phenylglycinol (2.5 equiv.) in
DCM at room temperature was sluggish but highly selective towards
the amino group, affording monoamidation product 11 (d.r.>20:1)
in 90% yield after 4 days. It was also determined if L-lysine
methyl ester (basic form) was able to provide high regioselectivity
in the ring opening reaction with 3c carried out in DCM. Indeed,
remarkable regiocontrol (at the terminal amino group) was achieved
in the formation of monoamide derivative 16 (90% yield of a single
diastereomer). The same regiocontrol was obtained in the reaction
of 2-azetine carboxylate 3c with L-lysine (4 equiv.) in THF/water
1:1 (v/v), but this reaction also resulted in hydrolysis of the
ester to the carboxylic acid (17, 75% yield) under the reaction
conditions. Reactions with tert-butylamine and pyrrolidine in
THF/water 1:1 (v/v), unlike that with benzylamine, resulted in
monoamidation and hydrolysis of the ester to form amidocarboxylic
acids 18 (80%) and 19 (72%), rather than in the formation of a
diamide.
As expected, the ring opening reactions of 2-azetine-2-carboxylates
with the weaker alcohol nucleophiles occurred at slower rates (FIG.
2A-). However, very high yields (up to 92%) of chiral diesters
20-22 were obtained with complete retention of enantiopurity from
the reactions of 3c, 3j, and 3k with methanol used as the solvent
at 65.degree. C. Use of higher molecular weight primary alcohols
resulted in a decrease of their reactivity with
2-azetine-2-carboxylates. The yield of diester 23 obtained with
ethanol (66%) at 65.degree. C. after 24 h was similar to that
obtained from the reaction with aniline (65%) but a much larger
excess of the nucleophile was used in this case (ethanol was used
as the solvent). Geraniol (a naturally occurring primary alcohol)
(Lei, Y., et al., Planta Med. 85, 48-55 (2019); Elsharif, S. A.
& Buettner, A., et al., J. Agric. Food Chem, 66, 2324-2333
(2018)) and ethylene glycol also formed the corresponding diesters
24 and 25 in moderate yields at 65.degree. C. after 24 h using only
4 equiv. of alcohol. In all reactions performed at elevated
temperatures, the main competing reaction was electrocyclic ring
opening of 2-azetine carboxylate 3c. (Lopez, S. A. & Houk, K.
N., et al., J. Org. Chem. 79, 6189-6195 (2014); Shindoh, N., et
al., J. Am. Chem. Soc., 133, 8470-8473 (2011); Mangelinckx, S. et
al.; J. Org. Chem., 73, 5481-5488 (2008)).
Besides amines, amino acids, alcohols, other relatively strong
nitrogen-based nucleophiles and tetrabutylammonium fluoride (TBAF)
have been tested (FIG. 3). The monomethyl ester of chiral
dicarboxylic acid 26 was obtained in 70% yield by a simple
treatment of 2-azetine-2-carboxylate 3c with a THE solution of
TBAF. Alternatively, compound 26 was obtained in near quantitative
yield by treatment of azetine 3c with 5 equiv. of water in
nitromethane at room temperature in 12 h. The reactivity of 3c with
phenylhydrazine was higher than that with aniline, and chiral
monohydrazide 27a was obtained in 87% yield at 50.degree. C. in DCE
after 12 h together with minor amounts (<10%) of the
electrocyclic ring opening product from 3c. The reaction of
electron-deficient 4-nitrophenylhydrazine with 3c in nitromethane
at room temperature resulted in high yield (88%) of the ring opened
product 27b. The use of aqueous solutions of hydroxylamine,
hydrazine, and ammonia for the reaction with 3c in THE led to the
formation of two C--N bonds and afforded chiral dihydroxamic acid
28, dihydrazide 29, and diamide 30 in excellent yields (up to 96%)
in 12 h. Efforts to perform selective reactions leaving the ester
group intact were not successful. An interesting example of
guanidine-based chiral peptide 31 was obtained in the reaction of
3c with guanidine in THF/water 1:1 (v/v). Use of 4 equiv. of
guanidine produced the zwitterionic peptide 27 in 78% isolated
yield. The product of the attachment of two molecules of guanidine
was detected in the reaction mixture by LC/MS but not isolated.
EXAMPLES
Example 1. Nucleophilic Ring Opening of Donor-Acceptor Azetines:
Mechanistic Studies
The discovery that the nucleophilic ring opening reaction carried
out in DCM requires two molecules of the nucleophile is based on:
(1) TIPS-Nuc was isolated as the by-product, and (2) only half of
the azetine was converted to product when 1 equiv. of the
nucleophile was used. It is not known if loss of the TIPS group and
ring opening are sequential or concerted, but it is proposed herein
that it is a sequential pathway to show all reaction intermediates,
including the 3-azetidiniones (FIG. 4A). The initial abstraction of
the silyl (TIPS) group by a nucleophile forms 2-azetine enol E, the
tautomer of which is 3-azetidinone carboxylate F. The carbonyl
group of F then undergoes attack by the second molecule of the
nucleophile to form zwitterionic four-membered ring intermediate G
followed by ring opening to the acyclic zwitterion H. Rapid
intramolecular proton abstraction by the carbanion forms the final
peptide structure. It was attempted to trap intermediate H using
benzyl bromide (5 equiv.) or methyl iodide (5-10 equiv.) as the
electrophile, but the absence of product from substitution
suggested a much higher rate for intramolecular proton transfer. To
support this mechanism, deuterium incorporation experiments were
carried out on the reaction of 3c with methanol-d.sub.4 used as the
solvent (FIG. 4B).
The reaction mechanism includes a set of intermediates I-L that are
the same to those shown in FIG. 4A. A preparative 0.2 mmol scale
ring opening reaction of 3c with methanol-d4 afforded deuterated
compound 32 in 92% isolated yield in 2 h without detection of
intermediates I-L by the NMR method.26 To investigate a possibility
of intermolecular proton transfer from intermediate H to the final
product we have performed a competing reaction of 3c with
benzylamine and methanol-d4 (FIG. 4C). The formation of 4 as the
major product confirmed the intramolecular proton transfer as the
major reaction pathway. However, minor amounts of deuterated
products were observed in the 1H NMR spectrum of the reaction
mixture as the result of deuterium exchange or incorporation from
methanol-d4, suggesting competition from intermolecular proton
transfer from methanol-d4 during the ring opening. Moreover,
diester 32 as the product of reaction of 3c with benzylamine and
MeOD was not observed in the reaction mixture.
Example 2. Functionalization of Ring Opened Products
To expand the scope of the ring opened products and the synthetic
applicability of the chlorine atom attached to the benzene ring,
the Suzuki-Miyaura sp.sup.2-sp.sup.2 cross-coupling with diamide 30
was performed (FIGS. 5A-5B). A compound containing a fluorine atom
(diamide 33) was obtained in 79% yield by treatment of diamide 30
with 4-fluorophenylboronic acid using the air and moisture stable
Buchwald's third generation precatalyst [a powerful source of
Pd(0)] (U.S. Pat. No. 8,889,857) that was synthesized from
commercially available precursors. Notably, amide functional groups
remained intact under these reaction conditions; however,
significant amounts of hydrolysis products were formed at
temperatures over 100.degree. C. (conversion of the amide to
carboxylates).
The use of fluorophores as sensors is common in chemical biology
(Lavis, L. D. & Raines, R. T., ACS Chem. Biol. 3, 142-155
(2008); Lavis, L. D. & Raines, R. T., ACS Chem. Biol., 9,
855-866 (2014)) and plays an important role in rapid detection of
peptides (Pazos, E., et al., Chem. Soc. Rev., 38, 3348-3359 (2009);
Kobayashi, H., et al., Chem. Rev., 110, 2620-2640 (2010); Lee, S.,
et al., Biochemistry, 49, 1364-1376 (2010); Staderinia, M., et al.,
Bioorg. Med. Chem., 26, 2816-2826 (2018)). Herein, a robust
protocol for the attachment of a fluorescent unit using the ring
opening reaction of azetine 3c with 4-aminoacridine as a
fluorophore-carrying nucleophile is disclosed. Bright yellow chiral
dipeptide 34 was obtained in high yield (74%) in nitromethane as
the most suitable solvent (FIG. 5B). The UV spectrum of 34 showed
maximum absorption at .lamda.=380, 399, and 421 nm; and the
fluorescence spectrum showed maximum emission at .lamda.=428, 453,
and 480 nm.
As shown in FIGS. 2A-2F, methanol and primary alcohols, but not
secondary alcohols, were suitable for the ring opening of azetines.
To solve the problem with secondary alcohols, a two-step protocol
was developed: synthesis of chiral monoester 26 and its reaction
with naturally-occurring secondary alcohols, cholesterol and
ergocalciferol (vitamin D.sub.2), using a classic base-catalysed
N,N'-dicyclohexylcarbodiimide (DCC) coupling reaction (FIG. 5D-5F).
Chiral diester derivatives 35 and 36 were obtained under mild
conditions in 78 and 84% yields, respectively, and the structure of
35 was confirmed by X-ray crystallography establishing the absolute
configuration of 26 as (R). This experimental evidence allowed the
assignment of absolute configurations of all chiral
materials--azetines and ring opened products.
The synthesis and transformations of chiral 3-azetidinones as
structural analogues of .beta.-lactams have not been previously
established. In this work, a highly effective synthetic route to
the precursor of this challenging structural unit through the
highly enantioselective [3+1]-cycloaddition of silyl-protected
enoldiazoacetates with aza-ylides using chiral copper(I) catalysis
was reported. The 2-azetidine cycloaddition products undergo
generation of 3-azetidinones by reactions with nucleophiles that
produce a broad spectrum of peptide products by the retro-Claisen
reaction provided by facile strain with high efficacy and complete
retention of enantiopurity. This ring opening reaction uncovers a
new methodology for the attachment of chiral peptide units to a
variety of amines and alcohols, and tolerates a broad scope of
nucleophiles including naturally occurring amines, alcohols, amino
acids, and other nitrogen based nucleophiles. Mechanistic studies
confirm the use of at least two equivalents of a nucleophile for
complete and efficient ring opening. Examples of the synthesis of
fluorescent dipeptides have been demonstrated using a nitrogen
based fluorescent nucleophile for the azetine ring opening. Further
functionalization of ring opened products has been successfully
performed in the Suzuki cross-coupling and in the esterification of
cholesterol and vitamin D2. The mild reaction conditions, high
enantiocontrol, broad scope of nucleophiles for the ring opening of
donor-acceptor azetines, and ability to perform the reaction in
aqueous media demonstrated in this work portray a process that will
have wide applications.
All references cited herein are incorporated by reference in their
entirety. The present invention may be embodied in other specific
forms without departing from the spirit or essential attributes
thereof and, accordingly, reference should be made to the appended
claims, rather than to the foregoing specification, as indicating
the scope of the invention.
* * * * *